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Romano, Michela; Della Porta, Matteo Giovanni; Gallì, Anna; Panini, Nicolò; Licandro, Simonetta Andrea; Bello, Ezia; Craparotta, Ilaria; Rosti, Vittorio; Bonetti, Elisa; Tancredi, Richard; Rossi, Marianna; Mannarino, Laura; Marchini, Sergio; Porcu, Luca; Galmarini, Carlos M; Zambelli, Alberto; Zecca, Marco; Locatelli, Franco; Cazzola, Mario; Biondi, Andrea; Rambaldi, Alessandro; Allavena, Paola; Erba, Eugenio; D'Incalci, Maurizio
British journal of cancer, 01/2017, Letnik: 116, Številka: 3Journal Article
Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN. Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines. On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models. Trabectedin could be good candidate for clinical studies in JMML/CMML patients.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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